The Bcl-2 family proteins are key effectors of cancers. Recent studies indicate that Myeloma cell factor-1 (Mcl-1), a member of this protein family, is a key regulator of lymphoid cancers including Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), and other cancers. Mcl-1 is regulated by distinct protein-protein interactions. Manipulation of these interactions using compounds that mimic the crucial binding domain, the BH3 domain, is a valid approach to developing oncology drugs. Efforts by commercial and academic groups have yielded several classes of compounds that target certain members of the Bcl-2 family. To date however, there has been no successful effort to develop a drug that targets Mcl-1. There is a clear unmet need for such a drug. In this application we propose the continued development of a novel compound that is highly active against Mcl-1. In our phase 1 study we identified a lead compound, characterized its in vitro and in vivo on-target activity, and demonstrated efficacy in a mouse xenograft model. We are now proceeding with a comprehensive med chem. optimization strategy that utilizes NMR analysis, computational modeling, and a novel mitochondrial assay that guide development of an IND candidate. We will also incorporate results from a small molecule library screen performed with The Scripps Institute Molecular Screening Center (TSIMSC) under a grant from the NIH Molecular Libraries Probe Center Network (MLPCN) to help further guide SAR and provide potential backup compounds. . Eutropics has assembled a highly competent team that is operating in our facility in Boston, MA. We have the active participation of SAB members Gerhard Wagner, Anthony Letai, and Ed Roberts, contributing expertise in, structural pharmacology, cancer cell biology/oncology, and translational medicinal chemistry. PUBLIC HEALTH RELEVANCE: Eutropics has assembled a strong science team further develop an anti-cancer therapeutic that targets the myeloid factor-1(Mcl-1) protein. Mcl-1 has been shown to be causal in certain cancers and is highly regarded as a drug target. In our SBIR phase I study we followed a plan to develop structure activity relationship (SAR) of early compounds and have identified a new lead compound. Our lead compound has activity against the target protein that is ten-fold more active than any such compounds reported. In vitro and in vivo studies support the development of this compound as a drug for treating multiple myeloma and other cancers. We describe our progress and plans for going forward, and we propose that this important work continue with SBIR phase II funding.